Differential activation of peroxisome proliferator-activated receptor-gamma by troglitazone and rosiglitazone.

Abstract

The antidiabetic thiazolidinediones, which include troglitazone and rosiglitazone, are ligands for the nuclear receptor peroxisome proliferator-a c t i v a t e d receptor (PPA R )-and exert their antihyperglycemic e ffects by regulation of PPA R--responsive genes. We report here that PPA R-activation by troglitazone depends on the experimental setting. Troglitazone acts as a partial agonist for PPA R-in transfected muscle (C2C12) and kidney (HEK 293T) cells, producing a submaximal transcriptional response (1.8-to 2.5-fold activation) compared with rosiglitazone (7.4-to 13-fold activation). Additionally, troglitazone antagonizes rosiglitazone-stimulated PPA R-transcriptional activity. Limited protease digestion of PPA R-suggests conformational differences in the receptor bound to troglitazone versus rosiglitazone. Consistent with this fin d i n g , an in vitro coactivator association assay demonstrated that troglitazone-bound PPA R-recruited the transcriptional coactivators p300 and steroid receptor coactivator 1 less efficiently than rosiglitazone-bound receptor. In contrast to these observations, troglitazone behaves as a full agonist of PPA R-in 3T3L1 adipocytes. Tw odimensional protein gel electrophoresis demonstrated that troglitazone and rosiglitazone regulated distinct but overlapping sets of genes in several cell types. Thus, troglitazone may behave as a partial agonist under certain physiological circumstances and as a full agonist in others. These differences could be caused by variations in the amount of specific cofactors, differences in PPA R response elements, or the presence of different isoforms of PPA R-. D i a b e t e s 4 9 :5 3 9-547, 2000 T ype 2 diabetes is characterized by decreased insulin sensitivity of peripheral tissues. Glucose homeostasis is maintained under these circumstances by increased insulin secretion from pancreatic -cells. In some cases, the -cell is unable to maintain increased output. The antidiabetic thiazolidinediones (TZDs), such as troglitazone, improve peripheral insulin sensitivity, leading to reduced blood glucose and insulin levels and the preservation of pancreatic function (1-4). Improvement of insulin sensitivity by TZDs is most likely due to the activation of the peroxisome proliferator-activated receptor (PPA R )-(5). The TZDs are high-affinity ligands for PPA R-in vitro, and the rank order of receptor affinity correlates with their in vivo hypoglycemic activity (6), with one reported exception (7). Although many of the molecular details are not clearly understood, a model has emerged in which activated PPA R-m o dulates the transcriptional activity of a set of genes encoding proteins that are important in glucose and lipid metabolism. H o w e v e r, the identity of these genes and the precise pathways leading to the normalization of insulin sensitivity remain largely unknown.R e c e n t l y, the X-ray crystal structure of the ligand-binding domain of PPA R-has been elucidated (3,8), revealing that ligand binding causes a conformational change within P PA R-such...

The new‐generation pan‐peroxisome proliferator‐activated receptor agonist IVA337 protects the liver from metabolic disorders and fibrosis

“…However, results with GW501516 in our study and in the literature differ from those obtained with KD3010, another PPARδ agonist that was shown to be very active on liver fibrosis induced by CCl 4 or bile duct ligation 39. This indicates that PPARδ‐mediated inhibition of fibrosis is likely to be ligand dependent owing to different pharmacokinetic properties or recruitment of different coregulators 39, 40…”

Pioglitazone, a Peroxisome Proliferator-Activated Receptor-γ Agonist, Attenuates Myocardial Ischemia/Reperfusion Injury in a Rat Model

“…It is, however, noteworthy that the potency of TZDs varies widely depending on the form of these compounds. Previous reports have demonstrated that troglitazone, one of the TZDs, shows differential activation of PPAR-␥ from rosiglitazone (Camp et al, 2000), suggesting that these two compounds cause a different recruitment of coactivator. The observation that TZDs can have distinct effects on the receptor raises the possibility that different PPAR-␥ ligands have distinct biologic downstream effects in different cell types.…”

Loss of XIAP sensitizes rosiglitazone‐induced growth inhibition of colon cancer in vivo

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